A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open I-Ks channels

BACKGROUND Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated. OBJECTIVE The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism. METHODS In 30 consecutive juvenile-onset AF patients (onset age <50 years), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations. RESULTS Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel., we focused on the proband. The G229D-I-Ks was found to induce a Large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-I-Ks (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-I-Ks, the tail current densities in WT/G229D-I-Ks were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-I-Ks resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-I-Ks conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-I-Ks results revealed that the mutation shortened atrial but not ventricular action potential. CONCLUSION A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the I-Ks activity and kinetics, thereby increasing the arrhythmogenicity to AF.